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Am J Physiol Endocrinol Metab (August 8, 2006). doi:10.1152/ajpendo.00617.2005
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Submitted on December 6, 2005
Accepted on July 21, 2006

Muscle Glucose Transport and Phosphorylation in Type 2 Diabetic, Obese Non-diabetic, and Genetically Predisposed Individuals

Merri Pendergrass1, Alessandra Bertoldo1, Riccardo C. Bonadonna1, Gianluca Nucci1, Lawrence Mandarino1, Claudio Cobelli1, and Ralph A DeFronzo1*

1 Medicine/Endocrinology, Harvard Medical School, Boston, United States

* To whom correspondence should be addressed. E-mail: albarado{at}uthscsa.edu.

Objectives: To quantitate insulin-stimulated inward glucose transport and glucose phosphorylation in forearm muscle in lean and obese nondiabetic subjects, in lean and obese type 2 diabetic (T2D) subjects, and in normal glucose tolerant, insulin resistant offspring of two T2D parents. Methods: Subjects received euglycemic insulin (40 mU/m2.min) clamp with brachial artery/deep forearm vein catheterization. After 120 minutes of hyperinsulinemia, a bolus of D-mannitol/3-0-[14C] methyl-D-glucose/D-[3-3H]-glucose (triple tracer technique) was given into brachial artery and deep vein samples obtained every 12-30 seconds for 15 minutes. Results: Insulin-stimulated forearm glucose uptake (FGU) and whole body glucose metabolism (M) were reduced by 40-50% in obese nondiabetic, lean diabetic, and obese diabetic subjects (all p<0.01); in offspring, the reduction in FGU and M was ~30% (p<0.05). Inward glucose transport and glucose phosphorylation were decreased by ~40-50% (p<0.01) in obese nondiabetic and diabetic groups and closely paralleled the decrease in FGU. The intracellular glucose concentration in the space accessible to glucose was significantly greater in obese nondiabetic, lean diabetic, obese diabetic and offspring compared to lean controls. Conclusions: (i) obese nondiabetic, lean T2D, and offspring manifest moderate-severe muscle insulin resistance (FGU and M) and decreased insulin-stimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus diabetes; (ii) the increase in intracelullar glucose concentration under hyperinsulinemic euglycemic conditions in obese and diabetic groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport.




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